This application requests a diversity supplement to support Dr. Debra Irsik as she completes portions of Project 1 of the Program Project (P01) award entitled ?Age-induced Impairment of Nutrient Signaling Results in Bone Loss?, while receiving training and mentoring to allow her to become an independent researcher in aging. Osteoporosis is a major public health problem affecting 44 million Americans. The estimated annual direct health-care cost for osteoporosis totaled $17 billion in 2001 and is rapidly rising. A critical barrier to correcting the problem of frailty and osteoporosis is a poor understanding of how nutrient-related stimuli and epigenetic mechanisms interact to induce bone and muscle loss. Our central hypothesis is that aging alters epigenetic regulatory systems (e.g., miRNA, acetylation) that act through nutrient signaling pathways on stem cells to affect musculoskeletal function. This is a highly integrated proposal from a group with an established track record of interactions, productivity and collaborations. Four individual projects, focused on epigenetic regulation and nutrient-related stimuli, comprise this application. The proposal also includes three Core facilities that will provide essential support to the Projects: an Administrative Core (Core A) that includes biostatistics and bioinformatics; a Bone Biology Core (Core B), which will provide the bone-specific techniques utilized by all the investigators; and a Bone Stem Cell Core (Core C) that will provide bone-derived cells to all investigators, including mouse and human bone marrow progenitor cells. The program project has three specific aims: Aim 1 will test the hypothesis that age-related changes in epigenetic signals alter musculoskeletal stem cell function; Aim 2 will test the hypothesis that specific dietary interventions (e.g., selective amino acid supplementation or intermittent fasting/protein feeding) can reverse age-related changes in epigenetic modifications and promote normal stem cell function; Aim 3 will test the hypothesis that relevant age-related epigenetic modifications identified in our mouse model are translatable to normal human physiology. The research to be performed by Dr. Irsik as part of Project #1 will (1) test the hypothesis that dietary supplementation with key amino acids can prevent or reverse aging-related impaired stem cell function in part through changes in miRNA expression and (2) determine the mechanism by which age-induced changes in amino acids, in particular elevated levels of kynurenine, an oxidized tryptophan metabolite, result in impaired function in BMSCs. The long-term impact of this project will be new findings on the epigenetic mechanisms underlying bone and muscle loss with age, and new countermeasures for reducing or reversing musculoskeletal aging. The more immediate impact of this project will be to provide Dr. Irsik with the opportunity to transition into aging research by obtaining preliminary data for submission of a career development award, as well as training and mentoring in aging research, in order to promote her development into an independent investigator in aging.